title: 3-Hydroxypyrimidine-2,4-diones as an inhibitor scaffold of HIV integrase.
abstract: Integrase (IN) represents a clinically validated target for the development of antivirals against human immunodeficiency virus (HIV). Inhibitors with a novel structure core are essential for combating resistance associated with known IN inhibitors (INIs). We have previously disclosed a novel dual inhibitor scaffold of HIV IN and reverse transcriptase (RT). Here we report the complete structure-activity relationship (SAR), molecular modeling, and resistance profile of this inhibitor type on IN inhibition. These studies support an antiviral mechanism of dual inhibition against both IN and RT and validate 3-hydroxypyrimidine-2,4-diones as an IN inhibitor scaffold.
authors.affiliation: Center for Drug Design, Academic Health Center, University of Minnesota, Minneapolis, Minnesota 55455, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Tang
authors.forename: Kasthuraiah
authors.initials: K
authors.lastname: Maddali
authors.forename: Mathieu
authors.initials: M
authors.lastname: Metifiot
authors.forename: Yuk Y
authors.initials: YY
authors.lastname: Sham
authors.forename: Robert
authors.initials: R
authors.lastname: Vince
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.forename: Zhengqiang
authors.initials: Z
authors.lastname: Wang
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D024882:Drug Resistance, Viral / Q000235:genetics; D006678:HIV / Q000187:drug effects / Q000201:enzymology*; D019427:HIV Integrase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D057927:Hydrophobic and Hydrophilic Interactions; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019428:HIV Integrase Inhibitors; D011743:Pyrimidines; D019427:HIV Integrase